Piperidinyl prostaglandin E analogs

ABSTRACT

The present invention provides a method of treating ocular hypertension or glaucoma which comprises administering to an animal having ocular hypertension or glaucoma therapeutically effective amount of a compound represented by the general formula I;                    
     wherein X, Y, Z, D and R 3  are as defined in the specification.

FIELD OF THE INVENTION

The present invention relates to piperidinyl prostaglandin E analogsuseful as therapeutic agents, e.g. ocular hypotensives that areparticularly suited for the management of glaucoma.

BACKGROUND OF THE INVENTION Description of Related Art

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior syncchia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical b-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives have been reported to possessocular hypotensive activity, and have been recommended for use inglaucoma management. Eicosanoids and derivatives include numerousbiologically important compounds such as prostaglandins and theirderivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2α))].

Prostaglandins were earlier regarded as potent ocular hypertensives,however, evidence accumulated in the last decade shows that someprostaglandins are highly effective ocular hypotensive agents, and areideally suited for the long-term medical management of glaucoma (see,for example, Bito, L. Z. Biological Protection with Prostaglandins,Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252;and Bito, L. Z., Applied Pharmacolopy in the Medical Treatment ofGlaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune &Stratton, 1984, pp. 477-505. Such prostaglandins include PGF_(2α),PGF_(1α), PGE₂, and certain lipid-soluble esters, such as C₁ to C₂ alkylesters, e.g. 1-isopropyl ester, of such compounds.

Although the precise mechanism is not yet known experimental resultsindicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et.al.,Invest. Ophthalmol. Vis. Sci. (suppl), 284 (1987)].

The isopropyl ester of PGF_(2α) has been shown to have significantlygreater hypotensive potency than the parent compound, presumably as aresult of its more effective penetration through the cornea. In 1987,this compound was described as “the most potent ocular hypotensive agentever reported” [see, for example, Bito, L. Z., Arch. Ophthalmol. 105,1036 (1987), and Siebold et.al., Prodrup 5 3 (1989)].

Whereas prostaglandins appear to be devoid of significant intraocularside effects, ocular surface (conjunctival) hyperemia and foreign-bodysensation have been consistently associated with the topical ocular useof such compounds, in particular PGF_(2α) and its prodrugs, e.g., its1-isopropyl ester, in humans. The clinical potentials of prostaglandinsin the management of conditions associated with increased ocularpressure, e.g. glaucoma are greatly limited by these side effects.

In a series of co-pending United States patent applications assigned toAllergan, Inc. prostaglandin esters with increased ocular hypotensiveactivity accompanied with no or substantially reduced side-effects aredisclosed. The co-pending U.S. Ser. No. 596,430 (filed Oct. 10, 1990,now U.S. Pat. No. 5,446,041), relates to certain 11-acyl-prostaglandins,such as 11-pivaloyl, 11-acetyl, 1-isobutyryl, 11-valeryl, and11-isovaleryl PGF_(2α). Intraocular pressure reducing 15-acylprostaglandins are disclosed in the co-pending application U.S. Ser. No.175,476. (filed Dec. 29, 1993). Similarly, 11,15-9,15 and 9,11-diestersof prostaglandins, for example 11,15-dipivaloyl PGF_(2α) are known tohave ocular hypotensive activity. See the co-pending patent applicationsU.S. Ser. No. 385,645 (filed Jul. 7, 1989, now U.S. Pat. No. 4,994,274),Ser. No. 584,370 (filed Sep. 18, 1990, now U.S. Pat. No. 5,028,624) andSer. No. 585,284 (filed Sep. 18, 1990, now U.S. Pat. No. 5,034,413). Thedisclosures of all of these patent applications are hereby expresslyincorporated by reference.

SUMMARY OF THE INVENTION

The present invention concerns piperidinyl prostaglandin E analogueswhich are useful in a method of treating ocular hypertension whichcomprises administering to a mammal having ocular hypertension atherapeutically effective amount of a compound of formula I

wherein hatched lines represent the α configuration, a trianglerepresents the β configuration, a wavy line represents either the αconfiguration or the β configuration and a dotted line represents thepresence or absence of a double bond;

D represents a covalent bond or CH₂, O, S or NH;

X is CO₂R, CONR₂, CH₂OR, P(O)(OR)₂, CONRSO₂R, SONR₂ or

Z is CH₂ or a covalent bond;

R is H or R²;

R¹ is H, R², phenyl, or COR²;

R² is C₁-C₅ lower alkyl or alkenyl and R³ is selected from the groupconsisting of

R², phenyl, thienyl, furanyl, pyridyl, benzothienyl, benzofuranyl,naphthyl, or substituted derivatives thereof, wherein the substituentsmaybe selected from the group consisting of C₁-C₅ alkyl, halogen, CF₃,CN, NO₂, NR₂, CO₂R and OR.

In a still further aspect, the present invention relates to apharmaceutical product, comprising

α container adapted to dispense its contents in a metered form; and

an ophthalmic solution therein, as hereinabove defined.

Finally, certain of the compounds represented by the above formula,disclosed below and utilized in the method of the present invention arenovel and unobvious.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of piperidinyl prostaglandin Etherapeutic agents, e.g. as analogs as ocular hypotensives. Thecompounds used in accordance with the present invention are encompassedby the following structural formula I:

The preferred group of the compounds of the present invention includescompounds that have the following structural formula II.

In the above formulae, the substituents and symbols are as hereinabovedefined.

In the above formulae:

Preferably Y is

Preferably D represents a covalent bond or is CH₂; more preferably D isCH₂ and R³ is n-propyl or D is a covalent bond and R³ is phenyl.

Preferably Z represents a covalent bond.

Preferably R is H or C₁-C₅ lower alkyl.

Preferably R¹ is H.

Preferably R³ is selected from the group consisting of phenyl andn-propyl.

Preferably X is CO₂R and more preferably R is selected from the groupconsisting of H and methyl.

The above compounds of the present invention may be prepared by methodsthat are known in the art or according to the working examples below.The compounds, below, are especially preferred representative, of thecompounds of the present invention.

7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acidmethyl ester

7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid

(Z)-7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-enoic acidmethyl ester

(Z)-7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-enoic acid

7-[2-oxo-6-(3-oxo-octyl)-piperidin-1-yl]-heptanoic acid methyl ester

7-[2-oxo-6-(3-oxo-octyl)-piperidin-1-yl]-heptanoic acid

7-[2-(3-hydroxy-octyl)-6-oxo-piperidin-1-yl]-heptanoic acid methyl ester

7-[2-(3-hydroxy-octyl)-6-oxo-piperidin-1-yl]-heptanoic acid

(Z)-7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid methyl ester

(Z)-7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid

7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid methylester

7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid

7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acidmethyl ester

7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid

7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoicacid methyl ester

7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoicacid

7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoicacid methyl ester

7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoicacid

7-[2-(3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-heptanoic acidmethyl ester

7-[2-(3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-heptanoic acid

7-[2-oxo-6-(3-oxo-4-phenyl-butyl)-piperidin-1-yl]-heptanoic acid methylester

7-[2-oxo-6-(3-oxo-4-phenyl-butyl)-piperidin-1-yl]-heptanoic acid

7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoicacid methyl ester

7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoicacid

(Z)-7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoicacid methyl ester

(Z)-7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoicacid

(Z)-7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid methyl ester

(Z)-7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid

Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound according tothe present invention, or a pharmaceutically acceptable acid additionsalt thereof, as an active ingredient, with conventional ophthalmicallyacceptable pharmaceutical excipients, and by preparation of unit dosageforms suitable for topical ocular use. The therapeutically efficientamount typically is between about 0.0001 and about 5% (w/v), preferablyabout 0.001 to about 1.0% (w/v) in liquid formulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 6.5 and 7.2with an appropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, although other chelating agents may also be used inplace or in conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustorq.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purifiedwater as needed to make 100%

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate the application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution.

This invention is further illustrated by the following non-limitingExamples.

EXAMPLE 1 7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoicacid methyl ester

Step 1

6-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-2-one

Imidazole (1.16 g, 17.0 mmol) and tert-butyldimethylsilyl chloride (1.18g, 7.85 mmol) were added sequentially to a solution of6-hydroxymethyl-piperidin-2-one (prepared from racemic α-aminoadipicacid according to Huang, et al., Synth. Commun. 1989, 19, Preparation ofOptically Pure ω-Hydroxymethyl Lactams, 3485-3496, 921 mg, 7.14 mmol) inDMF (10 mL) at 0° C. The reaction mixture was allowed to warm to rt andwas stirred at rt for 17 h. Benzene and EtOAc (3:7, 200 mL) was addedand the solution was washed with brine (3×50 mL). The organic phase wasdried (Na₂SO₄), filtered and concentrated in vacuo. Purification of theresidue by flash column chromatography on silica gel (CH₂Cl₂→3%MeOH/CH₂Cl₂, gradient) afforded 1.53 g (88%) of6-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-2-one as a whitesolid.

Step 2

7-[2-tert-butyl-dimethyl-silanyloxymethyl)-6-oxo-piperidin-1-yl]-hept-5-ynoicacid methyl ester

Sodium hydride (60% dispersion in oil, 219 mg, 5.27 mmol) was added to asolution of 6-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-2-one(1.27 g, 5.21 mmol) in DMF (10 mL) at rt. After 1 h, methyl7-iodohept-5-ynoate (1.52 g, 5.73 mmol) in DMF (2 mL) was added viacannula. After 18 h at rt, the reaction was quenched by the addition ofaqueous HCl (0.5 M, 15 mL) and the mixture was extracted with EtOAc(3×30 mL). The combined organic phase was washed with brine (3×20 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. Purification of theresidue by flash column chromatography on silica gel (CH₂Cl₂→40%EtOAc/CH₂Cl₂, gradient) afforded 1.04 g (53%) of7-[2-tert-butyl-dimethyl-silanyloxymethyl)-6-oxo-piperidin-1-yl]-hept-5-ynoicacid methyl ester.

Step 3

7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester

Hydrogen fluoride-pyridine (2.5 mL) was added to a solution of7-[2-tert-butyl-dimethyl-silanyloxymethyl)-6-oxo-piperidin-1-yl]-hept-5-ynoicacid methyl ester (1.07 g, 2.80 mmol) in acetonitrile (5.0 mL) in aplastic scintillation vial. After 3.5 h at rt, the reaction was quenchedwith saturated aqueous NaHCO₃ (70 mL) and the mixture was extracted withEtOAc (3×50 mL). The combined organic phase was washed with brine (50mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Purification ofthe residue by flash column chromatography on silica gel (CH₂Cl₂→3%MeOH/CH₂Cl₂, gradient) afforded 724 mg (97%) of7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester.

Step 4

7-(2-Formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester

1-(3-(Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 530mg, 2.76 mmol) and DMSO (0.26 mL, 3.68 mmol) were added sequentially toa solution of 7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acidmethyl ester (246 mg, 0.92 mmol) in benzene (7.0 mL) at rt. The mixturewas cooled to 0° C. and pyridinium trifluoroacetate (196 mg, 1.01 mmol)was added. The reaction was allowed to warm to rt and then was stirredat rt for 2.5 h. The solution was decanted from the oily residue and theresidue was washed with benzene (3×5 mL). The combined benzene phaseswere concentrated in vacuo to afford crude7-(2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester thatwas used without further purification.

Step 5

7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acidmethyl ester

Sodium hydride (60% dispersion in oil, 37 mg, 0.91 mmol) was added to asolution of dimethyl 2-oxoheptylphosphonate (217 mg, 0.83 mmol) in THF(4 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warmto rt. After 50 min at rt, the solution was recooled to 0° C. and7-(2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crudefrom previous reaction, ˜0.92 mmol) in THF (2 mL) was added via cannula.The reaction was allowed to warm to rt. After 18 h at rt, the reactionwas quenched with acetic acid and water (1:1, 15 mL) and extracted withEtOAc (3×40 mL). The combined organic phase was washed with brine (50mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Purification ofthe residue by flash column chromatography on silica gel (10% →50%EtOAc/CH₂Cl₂, gradient) afforded 175 mg (58%) of the title compound.

EXAMPLE 2 7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoicacid

Rabbit liver esterase (134 units/mg, 3 mg) was added to a solution of7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acidmethyl ester (18 mg, 0.45 mmol) in acetonitrile (0.3 mL) and pH 7.2phosphate buffer (3.0 mL). After 18.5 h, acetonitrile (10 mL) was addedand the reaction mixture was concentrated to dryness in vacuo.Purification of the residue by flash column chromatography on silica gel(CH₂Cl₂→3% MeOH/CH₂Cl₂, gradient) afforded 17 mg (97%) of the titlecompound.

EXAMPLE 3(Z)-7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-enoic acidmethyl ester

A 50 mL round bottom flask was charged with nickel (II) chloride (273mg, 2.10 mmol) and sodium borohydride (40 mg, 1.05 mmol), then 95%ethanol (2.0 mL) was added. The mixture immediately turned black. After15 min at rt, ethylene diamine (0.23 mL, 3.36 mmol) was added. Afteranother 15 min at rt,7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acidmethyl ester (152 mg, 0.42 mmol) in 95% ethanol (2.0 mL) was added viacannula. A hydrogen atmosphere was established by evacuating andrefilling with hydrogen (3×) and the reaction mixture was stirred undera balloon of hydrogen for 19 h. The reaction mixture was filteredthrough celite, washing with ethanol, and the filtrate was concentratedin vacuo. Purification of the resulting residue by flash columnchromatography (10→50% EtOAc/CH₂Cl₂, gradient) afforded 65 mg (43%) ofthe title compound.

EXAMPLE 4(Z)-7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-enoic acid

In accordance with the procedure of example 2,(Z)-7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-enoic acidmethyl ester (9 mg, 0.025 mmol) was converted into 5 mg (56%) of thetitle compound.

EXAMPLE 5 7-[2-oxo-6-(3-oxo-octyl)-piperidin-1-yl]-heptanoic acid methylester

Palladium on carbon (10 wt.%, 5 mg) was added to a solution of(Z)-7-[2-oxo-6-((E3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-enoic acidmethyl ester (40 mg, 0.11 mmol) in MeOH (3.0 mL). A hydrogen atmospherewas established by evacuating and refilling with hydrogen (3×) and thereaction mixture was stirred under a balloon of hydrogen for 19 h. Thereaction mixture was filtered through celite, washing with MeOH, and thefiltrate was concentrated in vacuo to afford 38 mg (94%) of the titlecompound.

EXAMPLE 6 7-[2-oxo-6-(3-oxo-octyl)-piperidin-1-yl]-heptanoic acid

In accordance with the procedure of example 2,7-[2-oxo-6-(3-oxo-octyl)-piperidin-1-yl]-heptanoic acid methyl ester (14mg, 0.038 mmol) was converted into 13 mg (97%) of the title compound.

EXAMPLE 7 7-[2-(3-hydroxy-octyl)-6-oxo-piperidin-1-yl]-heptanoic acidmethyl ester

Sodium borohydride (24 mg, 0.63 mmol), followed by MeOH (2 drops), wasadded to a solution of 7-[2-oxo-6-(3-oxooctyl)-piperidin-1-yl]-heptanoicacid methyl ester (23 mg, 0.063 mmol) in CH₂Cl₂ (1.0 ML) at 0° C. Themixture was allowed to warm to rt. After 4 h at rt, the reaction wasquenched with aqueous HCl (1.0 M) and extracted with EtOAc (3×10 mL).The combined organic phase was washed with saturated aqueous NaHCO₃ (15mL) and brine (15 mL) then dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the residue by flash column chromatography onsilica gel (CH₂Cl₂×3% MeOH/CH₂Cl₂, gradient) afforded 14 mg (61%) of thetitle compound.

EXAMPLE 8 7-[2-(3-hydroxy-octyl)-6-oxo-piperidin-1-yl]-heptanoic acid

In accordance with the procedure of example 2,7-[2-(3-hydroxy-octyl)-6-oxo-piperidin-1-yl]-heptanoic acid methyl ester(11.5 mg, 0.031 mmol) was converted into 6 mg (53%) of the titlecompound.

EXAMPLE 9(Z)-7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-hept-5enoicacid methyl ester

In accordance with the procedure of example 7,(Z)-7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-enoic acidmethyl ester (32 mg, 0.087 mmol) was converted into 25 mg (78%) of thetitle compound.

EXAMPLE 10(Z)-7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid

In accordance with the procedure of example 2,(Z)-7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid methyl ester (10 mg, 0.028 mmol) was converted into 5 mg (52%) ofthe title compound.

EXAMPLE 11 7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoicacid methyl ester

Step 1

7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester.

Palladium on carbon (10 wt.%, 20 mg) was added to a solution of7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester(180 mg, 0.67 mmol) in MeOH (6.0 mL). A hydrogen atmosphere wasestablished by evacuating and refilling with hydrogen (3×) and thereaction mixture was stirred under a balloon of hydrogen for 23 h. Thereaction mixture was filtered through celite, washing with MeOH, and thefiltrate was concentrated in vacuo to afford 184 mg (quant.) of7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester.

Step 2

7-(2-Formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester.

EDCI (212 mg, 1.10 mmol) and DMSO (0.10 mL, 1.48 mmol) were addedsequentially to a solution of7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester(100 mg, 0.37 mmol) in benzene (4.0 mL) at rt. The mixture was cooled to0° C. and pyridinium trifluoroacetate (79 mg, 0.41 mmol) was added. Thereaction was allowed to warm to rt and then was stirred at rt for 3.5 h.The solution was decanted from the oily residue and the residue waswashed with benzene (3×3 mL). The combined benzene phases wereconcentrated in vacuo to afford crude7-(2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester that wasused without further purification.

Step 3

7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid methylester

Sodium hydride (60% dispersion in oil, 15 mg, 0.37 mmol) was added to asolution of dimethyl 2-oxoheptylphosphonate (87 mg, 0.33 mmol) in THF (2mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm tort. After 1 h at rt, the solution was recooled to 0° C. and7-(2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crudefrom previous reaction, ˜0.37 mmol) in THF (2 mL) was added via cannula.The reaction was allowed to warm to rt. After 17 h at rt, the reactionwas quenched with acetic acid (50% aqueous, 20 mL) and extracted withEtOAc (3×20 mL). The combined organic phase was washed with saturatedaqueous NaHCO₃ (20 mL) and brine (20 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica gel (CH₂Cl₂→2% MeOH/CH₂Cl₂, gradient) afforded128 mg (95%) of the title compound.

EXAMPLE 12 7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoicacid

In accordance with the procedure of example 2,7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid methylester (17 mg, 0.048 mmol) was converted into 2 mg (12%) of the titlecompound after flash column chromatography on silica gel (CH₂Cl₂→2%MeOH/CH₂Cl₂, gradient) and preparative thin layer chromatography(silica, 5% MeOH/CH₂Cl₂).

EXAMPLE 137-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acidmethyl ester

Sodium borohydride (42 mg, 1.10 mmol), followed by MeOH (0.38 mL), wasadded to a solution of7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid methylester (40 mg, 0.11 mmol) in CH₂Cl₂ (1.13 mL) at 0° C. The mixture wasallowed to warm to rt. After 3 h at rt, the reaction was quenched withaqueous HCl (1.0 M) and extracted with EtOAc (3×10 mL). The combinedorganic phase was washed with brine (20 mL) then dried (Na₂SO₄),filtered and concentrated in vacuo to afford 40 mg (99%) of the titlecompound.

EXAMPLE 147-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid

In accordance with the procedure of example 2,7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acidmethyl ester (18 mg, 0.049 mmol) was converted into 6 mg (35%) of thetitle compound.

EXAMPLE 157-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoicacid methyl ester

Sodium hydride (60% dispersion in oil, 12 mg, 0.32 mmol) was added to asolution of dimethyl 2-oxo-3-phenylpropylphosphonate (70 mg, 0.29 mmol)in THF (1.5 mL) at 0° C. After 10 min at 0° C., the solution was allowedto warm to rt. After 50 min at rt, the solution was recooled to 0° C.and 7-(2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester(crude, prepared in accordance with example 11, step 2, ˜0.32 mmol) inTHF (1.5 mL) was added via cannula. The reaction was allowed to warm tort. After 18 h at rt, the reaction was quenched with acetic acid (50%aqueous, 20 mL) and extracted with EtOAc (30×20 mL). The combinedorganic phase was washed with saturated aqueous NaHCO₃ (30 mL) and brine(30 mL), dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(CH₂Cl₂→2% MeOH/CH₂Cl₂, gradient) afforded 66 mg (59%) of the titlecompound.

EXAMPLE 167-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoicacid

In accordance with the procedure of example 2,7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoicacid methyl ester (7 mg, 0.018 mmol) was converted into 2 mg (30%) ofthe title compound.

EXAMPLE 177-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoicacid methyl ester

Sodium borohydride (36 mg, 0.96 mmol), followed by MeOH (0.25 mL), wasadded to a solution of7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoicacid methyl ester (37 mg, 0.096 mmol) in CH₂Cl₂ (0.75 mL) at 0° C. Themixture was allowed to warm to rt. After 1.5 h at rt, the reaction wasquenched with aqueous HCl (1.0 M) and extracted with EtOAc (30×10 mL).The combined organic phase was washed with saturated aqueous NaHCO₃ (20mL) and brine (20 mL) then dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the residue by flash column chromatography onsilica gel (CH₂Cl₂→3% MeOH/CH₂Cl₂, gradient) afforded 32 mg (86%) of thetitle compound.

EXAMPLE 187-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoicacid

In accordance with the procedure of example 2,7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoicacid methyl ester (10 mg, 0.026 mmol) was converted into 6.6 mg (68%) ofthe title compound.

EXAMPLE 197-[2-(3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-heptanoic acidmethyl ester

Palladium on carbon (10 wt.%, 5 mg) was added to a solution of7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoicacid methyl ester (20 mg, 0.052 mmol) in MeOH (2.0 mL). A hydrogenatmosphere was established by evacuating and refilling with hydrogen(3×) and the reaction mixture was stirred under a balloon of hydrogenfor 22 h. The reaction mixture was filtered through celite, washing withMeOH, and the filtrate was concentrated in vacuo to afford 13 mg (65%)of the title compound.

EXAMPLE 207-[2-(3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-heptanoic acid

In accordance with the procedure of example 2,7-[2-(3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-heptanoic acidmethyl ester (11 mg, 0.029 mmol) was converted into 3.5 mg (32%) of thetitle compound.

EXAMPLE 21 7-[2-oxo-6-(3-oxo-4-phenyl-butyl)-piperidin-1-yl]-heptanoicacid methyl ester

In accordance with the procedure of example 19,7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoicacid methyl ester (20 mg, 0.052 mmol) was converted into 15 mg (75%) ofthe title compound.

EXAMPLE 22 7-[2-oxo-6-(3-oxo-4-phenyl-butyl)-piperidin-1-yl]-heptanoicacid

In accordance with the procedure of example 2,7-[2-oxo-6-(3-oxo-4-phenyl-butyl)-piperidin-1-yl]-heptanoic acid methylester (12 mg, 0.031 mmol) was converted into 2.8 mg (24%) of the titlecompound.

EXAMPLE 237-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoicacid methyl ester

Sodium hydride (60% dispersion in oil, 23 mg, 0.58 mmol) was added to asolution of dimethyl 2-oxo-3-phenylpropylphosphonate (171 mg, 0.64 mmol)in THF (2.0 mL) at 0° C. After 10 min at 0° C., the solution was allowedto warm to rt. After 50 min at rt, the solution was recooled to 0° C.and 7-(2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester(crude, prepared in accordance with example 1, step 4, ˜0.64 mmol) inTHF (2.0 mL) was added via cannula. The reaction was allowed to warm tort. After 18 h at rt, the reaction was quenched with acetic acid (50%aqueous, 20 mL) and extracted with EtOAc (30×20 mL). The combinedorganic phase was washed with saturated aqueous NaHCO₃ (30 mL) and brine(30 mL), dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica geltwice (1^(st) CH₂Cl₂→2% MeOH/CH₂Cl₂, gradient and 2^(nd) CH₂Cl₂→30%EtOAc/CH₂Cl₂, gradient) afforded 51 mg (21%) of the title compound.

EXAMPLE 247-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoicacid

In accordance with the procedure of example 2,7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoicacid methyl ester (9 mg, 0.024 mmol) was converted into 1.4 mg (16%) ofthe title compound.

EXAMPLE 25(Z)-7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoicacid methyl ester

A round bottom flask was charged with nickel (II) chloride (68 mg, 0.52mmol) and sodium borohydride (9.9 mg, 0.26 mmol), then 95% ethanol (1.0mL) was added. The mixture immediately turned black. After 15 min at rt,ethylene diamine (56 μL, 0.84 mmol) was added. After another 15 min atrt,7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoicacid methyl ester (40 mg, 0.10 mmol) in 95% ethanol (1.0 mL) was addedvia cannula. A hydrogen atmosphere was established by evacuating andrefilling with hydrogen (3×) and the reaction mixture was stirred undera balloon of hydrogen for 18 h. The reaction mixture was filteredthrough celite, washing with ethanol, and the filtrate was concentratedin vacuo. Purification of the resulting residue by flash columnchromatography (CH₂Cl₂→30% EtOAc/CH₂Cl₂, gradient) afforded 28 mg (70%)of the title compound.

EXAMPLE 26(Z)-7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoicacid

In accordance with the procedure of example 2,(Z)-7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoicacid methyl ester (9.2 mg, 0.024 mmol) was converted into 8 mg (90%) ofthe title compound.

EXAMPLE 27(Z)-7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid methyl ester

Sodium borohydride (16 mg, 0.42 mmol), followed by MeOH (0.25 mL), wasadded to a solution of(Z)-7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoicacid methyl ester (16 mg, 0.042 mmol) in CH₂Cl₂ (0.75 mL) at 0° C. Themixture was allowed to warm to rt. After 2.5 h at rt, the reaction wasquenched with aqueous HCl (1.0 M) and extracted with EtOAc (3→15 mL).The combined organic phase was washed with saturated aqueous NaHCO₃ (15mL) and brine (15 mL) then dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the residue by flash column chromatography onsilica gel (CH₂Cl₂→50% EtOAc/CH₂Cl₂, gradient) afforded 10 mg (62%) ofthe title compound.

EXAMPLE 28(Z)-7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid

In accordance with the procedure of example 2,(Z)-7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid methyl ester (8.5 mg, 0.022 mmol) was converted into 2.4 mg (29%)of the title compound.

These compounds are tested for in vitro activity as described below andthe results given in the Table.

TABLE Ex- Binding Data Functional Data (EC50 in am- (IC50 in nM) nM) pleStructure hEP2 hEP30 hEP4 hFP hEP1 hEP2 hEP3A hEP4 hTP hP hDP  1

NA NA NA NA NA >10000 NA  2

NA NA NA NA NA NA  3

NA NA NA NA NA NA  4

NA NA NA NA  10000 NA  5

NA NA NA NA NA >10000 NA  6

NA NA NA NA >10000 NA  7

NA NA NA NA  1842 >10000 NA  8

NA NA >10000   99  9

NA NA NA NA   815 >10000 NA 10

NA >10000 NA   46 NA 11

NA NA NA NA NA >10000 NA 12

NA NA NA NA NA 13

NA NA NA NA NA NA 14

NA NA NA >10000 15

NA NA NA NA NA >10000 NA 16

NA NA NA NA >10000 NA 17

NA NA NA NA NA NA 18

NA NA NA NA NA 19

NA NA NA NA NA >10000 NA 20

NA NA NA NA NA 21

22

23

24

25

26

27

Human Recombinant EP₁, EP₂, EP₃, EP₄, FP, TP, IP and DP Receptors:Stable Transfectants

Plasmids encoding the human EP₁, EP₂, EP₃, EP₄, FP, TP, IP and DPreceptors were prepared by cloning the respective coding sequences intothe eukaryotic expression vector pCEP4 (Invitrogen). The pCEP4 vectorcontains an Epstein Barr virus (EBV) origin of replication, whichpermits episomal replication in primate cell lines expressing EBVnuclear antigen (EBNA-1). It also contains a hygromycin resistance genethat is used for eukaryotic selection. The cells employed for stabletransfection were human embryonic kidney cells (HEK-293) that weretransfected with and express the EBNA-1 protein. These HEK-293-EBNAcells (Invitrogen) were grown in medium containing Geneticin (G418) tomaintain expression of the EBNA-1 protein. HEK-293 cells were grown inDMEM with 10% fetal bovine serum (FBS), 250 μg ml⁻¹ G418 (LifeTechnologies) and 200 μg ml⁻¹ gentamicin or penicillin/streptomycin.Selection of stable transfectants was achieved with 200 μg ml⁻¹hygromycin, the optimal concentration being determined by previoushygromycin kill curve studies.

For transfection, the cells were grown to 50-60% confluency on 10 cmplates. The plasmid pCEP4 incorporating cDNA inserts for the respectivehuman prostanoid receptor (20 μg) was added to 500 μl of 250 mM CaCl₂.HEPES buffered saline ×2 (2×HBS, 280 mM NaCl, 20 mM HEPES acid, 1.5 mMNa₂ HPO₄, pH 7.05-7.12) was then added dropwise to a total of 500 μl,with continuous vortexing at room temperature. After 30 min, 9 ml DMEMwere added to the mixture. The DNA/DMEM/calcium phosphate mixture wasthen added to the cells, which had been previously rinsed with 10 mlPBS. The cells were then incubated for 5 hr at 37° C. in humidified 95%air/5% CO₂. The calcium phosphate solution was then removed and thecells were treated with 10% glycerol in DMEM for 2 min. The glycerolsolution was then replaced by DMEM with 10% FBS. The cells wereincubated overnight and the medium was replaced by DMEM/10% FBScontaining 250 μg ml⁻¹ G418 and penicillin/streptomycin. The followingday hygromycin B was added to a final concentration of 200 μg ml⁻¹.

Ten days after transfection, hygromycin B resistant clones wereindividually selected and transferred to a separate well on a 24 wellplate. At confluence each clone was transferred to one well of a 6 wellplate, and then expanded in a 10 cm dish. Cells were maintained undercontinuous hygromycin selection until use.

Radioligand Binding

Radioligand binding studies on plasma membrane fractions prepared forcells stably transfected with the cat or human receptor were performedas follows. Cells washed with TME buffer were scraped from the bottom ofthe flasks and homogenized for 30 sec using a Brinkman PT 10/35polytron. TME buffer was added as necessary to achieve a 40 ml volume inthe centrifuge tubes. TME is comprised of 50 mM TRIS base, 10 mM MgCl₂,1 mM EDTA; pH 7.4 is achieved by adding 1 N HCl. The cell homogenate wascentrifuged at 19,000 rpm for 20-25 min at 4° C. using a Beckman Ti-60or Tt-70 rotor. The pellet was then resuspended in TME buffer to providea final protein concentration of 1 mg/ml, as determined by Bio-Radassay. Radioligand binding assays were performed in a 100 μl or 200 μlvolume.

The binding of [³H](N) PGE₂ (specific activity 165 Ci/mmol) wasdetermined in duplicate and in at least 3 separate experiments.Incubations were for 60 min at 25° C. and were terminated by theaddition of 4 ml of ice-cold 50 mM TRIS-HCl followed by rapid filtrationthrough Whatman GF/B filters and three additional 4 ml washes in a cellharvester (Brandel). Competition studies were performed using a finalconcentration of 2.5 or 5 nM [³H](N) PGE₂ and non-specific binding wasdetermined with 10⁻⁵ M unlabelled PGE₂.

For radioligand binding on the transient transfectants, plasma membranefraction preparation was as follows. COS-7 cells were washed with TMEbuffer, scraped from the bottom of the flasks, and homogenized for 30sec using a Brinkman PT 10/35 polytron. TME buffer was added to achievea final 40 ml volume in the centrifuge tubes. The composition of TME is100 mM TRIS base, 20 mM MgCl₂, 2M EDTA; 10N HCl is added to achieve a pHof 7.4.

The cell homogenate was centrifuged at 19000 rpm for 20 min at 4° C.using a Beckman Ti-60 rotor. The resultant pellet was resuspended in TMEbuffer to give a final 1 mg/ml protein concentration, as determined byBiorad assay. Radioligand binding assays were performed in a 200 μlvolume.

The binding of [³H] PGE₂ (specific activity 165 Ci or mmol⁻¹) atEP_(3D), receptors and [³H]-SQ29548 (specific activity 41.5 Ci mmol⁻¹)at TP receptors were determined in duplicate in at least three separateexperiments. Radiolabeled PGE₂ was purchased from Amersham, radiolabeledSQ29548 was purchased from New England Nuclear. Incubations were for 60min at 25° C. and were terminated by the addition of 4 ml of ice-cold 50mM TRIS-HC1, followed by rapid filtration through Whatman GF/B filtersand three additional 4 ml washes in a cell harvester (Brandel).Competition studies were performed using a final concentration of 2.5 or5 nM [³H]-PGE₂, or 10 nM [³H]-SQ 29548 and non-specific bindingdetermined with 10 μM of the respective unlabeled prostanoid. For allradioligand binding studies, the criteria for inclusion were >50%specific binding and between 500 and 1000 displaceable counts or better.

The effects of the compounds of this invention on intraocular pressuremay be measured as follows. The compounds are prepared at the desiredconcentrations in a vehicle comprising 0.1% polysorbate 80 and 10 mMTRIS base. Dogs are treated by administering 25 μl to the ocularsurface, the contralateral eye receives vehicle as a control.Intraocular pressure is measured by applanation pneumatonometry. Dogintraocular pressure is measured immediately before drug administrationand at 6 hours thereafter.

The compounds of this invention are useful in lowering elevatedintraocular pressure in mammals, e.g. humans.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

What is claimed is:
 1. A method of treating ocular hypertension orglaucoma which comprises administering to an animal having ocularhypertension or glaucoma a therapeutically effective amount of acompound represented by the general formula

wherein hatched lines represent the α configuration, a trianglerepresents the β configuration, a wavy line represents either the αconfiguration or the β configuration and a dotted line represents thepresence or absence of a double bond; D represents a covalent bond orCH₂, O, S or NH; X is CO₂R, CONR₂, CH₂OR, P(O)(OR)₂, CONRSO₂R, SONR₂ or

Z is CH₂ or a covalent bond; R is H or R²; R¹ is H, R², phenyl, or COR²;R² is C₁-C₅ lower alkyl or alkenyl and R₃ is selected from the groupconsisting of R², phenyl, thienyl, furanyl, pyridyl, benzothienyl,benzofuranyl, naphthyl, or substituted derivatives thereof, wherein thesubstituents maybe selected from the group consisting of C₁-C₅ alkyl,halogen, CF₃, CN, NO₂, NR2, CO₂R and OR.
 2. The method according toclaim 1 wherein said compound is represented by the general formula II;


3. The method of claim 1 wherein Z represents a covalent bond.
 4. Themethod of claim 1 wherein D is CH₂.
 5. The method of claim 1 wherein Xis CO₂R.
 6. The method of claim 5 wherein R is selected from the groupconsisting of H and methyl.
 7. The method of claim 5 wherein R is H, orC₁-C₅ alkyl.
 8. The method of claim 1 wherein R₁ is H.
 9. The method ofclaim 1 wherein R³ is selected from the group consisting of phenyl andn-propyl.
 10. The method of claim 1 wherein said compound is selectedfrom the group consisting of7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acidmethyl ester,7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid,(Z)-7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-enoic acidmethyl ester,(Z)-7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-enoic acid,7-[2-oxo-6-(3-oxo-octyl)-piperidin-1-yl]-heptanoic acid methyl ester,7-[2-oxo-6-(3-oxo-octyl)-piperidin-1-yl]-heptanoic acid,7-[2-(3-hydroxy-octyl)-6-oxo-piperidin-1-yl]-heptanoic acid methylester, 7-[2-(3-hydroxy-octyl)-6-oxo-piperidin-1-yl]-heptanoic acid,(Z)-7-[2(E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid methyl ester,(Z)-7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid, 7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acidmethyl ester,7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid,7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acidmethyl ester,7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid,7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoicacid methyl ester,7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoicacid,7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoicacid methyl ester,7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoicacid, 7-[2-(3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-heptanoicacid methyl ester,7-[2-(3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-heptanoic acid,7-[2-oxo-6-(3-oxo-4-phenyl-butyl)-piperidin-1-yl]-heptanoic acid methylester, 7-[2-oxo-6-(3-oxo-4-phenyl-butyl)-piperidin-1-yl]-heptanoic acid,7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoicacid methyl ester,7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoicacid,(Z)-7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoicacid methyl ester,(Z)-7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoicacid,(Z)-7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid methyl ester and(Z)-7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid.
 11. A compound represented by the general formula I;

wherein hatched lines represent the α configuration, a trianglerepresents the β configuration, a wavy line represents either the αconfiguration or the β configuration and a dotted line represents thepresence or absence of a double bond; D represents a covalent bond orCH₂, O, S or NH; X is CO₂R, CONR₂, CH₂OR, P(O)(OR)₂, CONRSO₂R, SONR₂ or

Z is CH₂ or a covalent bond; R is H or R²; R¹ is H, R², phenyl, or COR²;R² is C₁-C₅ lower alkyl or alkenyl and R₃ is selected from the groupconsisting of R², phenyl, thienyl, furanyl, pyridyl, benzothienyl,benzofuranyl, naphthyl, or substituted derivatives thereof, wherein thesubstituents maybe selected from the group consisting of C₁-C₅ alkyl,halogen, CF₃, CN, NO₂, NR₂, CO₂R and OR.
 12. The compound according toclaim 11 wherein said compound is represented by the general formula II;


13. The compound of claim 11 wherein Z represents a covalent bond. 14.The compound of claim 11 wherein D is CH₂.
 15. The compound of claim 11wherein X is CO₂R.
 16. The compound of claim 15 wherein R is selectedfrom the group consisting of H and methyl.
 17. The compound claim 15wherein R is H, or C₁-C₅ alkyl.
 18. The compound of claim 11 wherein R₁is H.
 19. The compound of claim 11 wherein R³ is selected from the groupconsisting of phenyl and n-propyl.
 20. The compound of claim 11 whereinsaid compound is selected from the group consisting of7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acidmethyl ester,7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid,(Z)-7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-enoic acidmethyl ester,(Z)-7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-enoic acid,7-[2-oxo-6-(3-oxo-octyl)-piperidin-1-yl]-heptanoic acid methyl ester,7-[2-oxo-6-(3-oxo-octyl)-piperidin-1-yl]-heptanoic acid,7-[2-(3-hydroxy-octyl)-6-oxo-piperidin-1-yl]-heptanoic acid methylester, 7-[2-(3-hydroxy-octyl)-6-oxo-piperidin-1-yl]-heptanoic acid,(Z)-7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid methyl ester,(Z)-7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid, 7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acidmethyl ester,7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid,7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acidmethyl ester,7-[2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid,7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoicacid methyl ester,7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoicacid,7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoicacid methyl ester,7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoicacid, 7-[2-(3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-heptanoicacid methyl ester,7-[2-(3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-heptanoic acid,7-[2-oxo-6-(3-oxo-4-phenyl-butyl)-piperidin-1-yl]-heptanoic acid methylester, 7-[2-oxo-6-(3-oxo-4-phenyl-butyl)-piperidin-1-yl]-heptanoic acid,7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoicacid methyl ester,7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoicacid,(Z)-7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoicacid methyl ester,(Z)-7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoicacid,(Z)-7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid methyl ester and(Z)-7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-enoicacid.
 21. An ophthalmic solution comprising a therapeutically effectiveamount of a compound represented by the general Formula 1

wherein hatched lines represent the α configuration, a trianglerepresents the β configuration, a wavy line represents the αconfiguration or the β configuration and a dotted line represents thepresence or absence of a double bond; D represents a covalent bond orCH₂, O, S or NH; X is C O₂R, CONR₂, CH₂OR, P(O)(OR)₂, CONRSO₂R SONR₂ or

Z is CH₂ or a covalent bond; R is H or R²; R¹ is H, R², phenyl, or COR²;R² is C₁-C₅ lower alkyl or alkenyl and R₃ is selected from the groupconsisting of R², phenyl, thienyl, furanyl, pyridyl, benzothienyl,benzofuranyl, naphthyl or substituted derivatives thereof, wherein thesubstituents maybe selected from the group consisting of C₁-C₅ alkyl,halogen, CF₃, CN, NO₂, NR₂, CO₂R and OR in admixture with a non-toxic,ophthalmically acceptable liquid vehicle, packaged in a containersuitable for metered application.